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Gao B.,National Human Genome Research Institute
Current Topics in Developmental Biology

Planar cell polarity (PCP), a process controlling coordinated, uniformly polarized cellular behaviors in a field of cells, has been identified to be critically required for many fundamental developmental processes. However, a global directional cue that establishes PCP in a three-dimensional tissue or organ with respect to the body axes remains elusive. In vertebrate, while Wnt-secreted signaling molecules have been implicated in regulating PCP in a β-catenin-independent manner, whether they function permissively or act as a global cue to convey directional information is not clearly defined. In addition, the underlying molecular mechanism by which Wnt signal is transduced to core PCP proteins is largely unknown. In this chapter, I review the roles of Wnt signaling in regulating PCP during vertebrate development and update our knowledge of its regulatory mechanism. © 2012 Elsevier Inc. Source

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB–mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB–dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease. © 2015 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. Source

Manolio T.A.,National Human Genome Research Institute
New England Journal of Medicine

Over the past 5 years, genomewide association studies have yielded a wealth of insight into genes and chromosomal loci that contribute to susceptibility to disease. This article, the second in the Genomic Medicine series, describes the design of these studies and considers the extent to which the data they provide are useful in predicting the risk of disease. Copyright © 2010 Massachusetts Medical Society. Source

Manolio T.A.,National Human Genome Research Institute
Nature Reviews Genetics

Genome-wide association studies (GWASs) have been heralded as a major advance in biomedical discovery, having identified ~2,000 robust associations with complex diseases since 2005. Despite this success, they have met considerable scepticism regarding their clinical applicability; this scepticism arises from such aspects as the modest effect sizes of associated variants and their unclear functional consequences. There are, however, promising examples of GWAS findings that will or that may soon be translated into clinical care. These examples include variants identified through GWASs that provide strongly predictive or prognostic information or that have important pharmacological implications; these examples may illustrate promising approaches to wider clinical application. © 2013 Macmillan Publishers Limited. All rights reserved. Source

Aksentijevich I.,National Human Genome Research Institute
Seminars in Immunopathology

Autoinflammatory diseases are a genetically heterogeneous group of rheumatologic diseases that are driven by abnormal activation of the innate immune system. Patients present with recurrent episodes of systemic inflammation and a spectrumof organ-specific comorbidities. These diseases are mediated by the overproduction of various inflammatory cytokines, such as IL-1, IL-18, IL-6, TNFα, and type I interferon. Treatments with biologic agents that inhibit these cytokines have been very efficient in most patients. During the past 2 years, remarkable progress has been made in the identification of disease-associated genes owing mostly to new technologies. Next generation sequencing technologies (NGS) have become instrumental in finding single-gene defects in undiagnosed patients with early onset symptoms. NGS has advanced the field of autoinflammation by identifying disease-causing genes that point to pathways not known to regulate cytokine signaling or inflammation. They include a protein that has a role in differentiation of myeloid cells, a ubiquitously expressed enzyme that catalyzes the addition of the CCA terminus to the 3-prime end of tRNA precursors, and an enzyme that catalyzes the oxidation of a broad range of substrates. Lastly, newly described mutations have informed a whole new dimension on genotype-phenotype relationships. Mutations in the same gene can give rise to a range of phenotypes with a common inflammatory component. This suggests greater than anticipated contributions by modifying alleles and environmental factors to disease expressivity. © Springer-Verlag (outside the USA) 2015. Source

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